Mohd Mustapa M Firouz, Harris Richard, Bulic-Subanovic Nives, Elliott Susan L, Bregant Sarah, Groussier Marianne F A, Mould Jessica, Schultz Darren, Chubb Nathan A L, Gaffney Piers R J, Driscoll Paul C, Tabor Alethea B
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H OAJ UK.
J Org Chem. 2003 Oct 17;68(21):8185-92. doi: 10.1021/jo0346398.
Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.
羊毛硫抗生素是一类硫醚桥连的抗菌肽，其合成方法需要灵活的合成路线来制备多种正丙氨酸1的正交保护衍生物。合成正丙氨酸最直接的方法是使半胱氨酸与丙氨酰β-阳离子类似物反应。丙氨酰β-阳离子类似物有几种可能，包括在 Mitsunobu 条件下直接活化丝氨酸：然而，硫亲核试剂在 Mitsunobu 反应中的低反应活性此前使其无法用于羊毛硫抗生素的合成。我们在此报道一种合成保护正丙氨酸 的新方法，该方法使用 Mitsunobu 反应的一种新型变体，其中使用催化量的酒石酸锌来增强硫醇的亲核性。在这些研究过程中，我们还证明了从三苯甲基保护的β-碘代丙氨酸合成正丙氨酸容易通过氮丙啶重排，主要生成三苯甲基保护的α-碘代β-丙氨酸，因此主要产物为去甲正丙氨酸。
